The main cause for therapeutic failure of cancer in a human is multidrug resistance (MDR) which refers to development of resistance of cancer cells to anticancer drugs entirely different in terms of structure or mechanism and is closely connected with the overexpression of a transport protein known as P-glycoprotein (P-gp). P-gp is an ATP-dependent transport protein involved in cellular efflux of a wide variety of fat-soluble substances including anticancer drugs. P-gp lowers a concentration of a therapeutic drug in cancer cells, resulting in increased drug resistance of the cancer cells (Juranka et al., FASEB J., 3, pp 2583-2592, 1989; Fuqua et al., Cancer Res., 47, pp 2103-2106, 1987; Endicott et al., Ann. Rev. Biochem., 58, pp 137-171, 1989; and Gottesman et al., Ann. Rev. Biochem, 62, pp 385-427, 1993). Further, it is known that P-gp is also present in diverse normal organs such as liver, small intestines, kidney and brain and serves a cellular defense function by cellular efflux of toxic substances introduced to the living body (Theibaut et al., Proc. Natl. Acad. Sci., 84, pp 7735-7738, 1987; Lum et al., Hematol. Oncol. Clin. North Am., 9 pp 319-336, 1995; M. F. Fromm, Int. J. Clin. Pharmacol. Ther., 38, pp 69-74, 2000; and Stenkampf et al., Cancer Res., 48 pp 3025-3030, 1988).
Meanwhile, it is currently known that high intake of fruits or vegetables leads to a decrease in risk of carcinogenesis (J. D. Potter, Cancer Lett., 114, pp 7-9, 1997; and M. J. Wargovich, Cancer Lett., 114, pp 11-17, 1997). There has been reported that a diversity of ingredients derived from natural substances is implicated in modulation of the activity of P-gp in in vitro human cancer cells and in vivo animal models (Scambia et al., Cancer Chemother. Pharmacol., 34, pp 459-464, 1994; Chieli et al., Life Sci., pp 1741-1751, 1995; Ikegawa et al., Cancer lett., 177, pp 89-93, 2002; Zhou et al., Drug Metab Rev, 36 pp 57-104, 2004; Chung et al., Phytother Res, 21, pp 565-569, 2007; and Chung et al., Phytother Res, 23, pp 472-476, 2009). Further, there has been reported that flavonoids have an effect on P-gp-induced efflux of dimethylbenz[α]anthracene, benzo[α]pyrene and adriamycin (Yeh et al., Cancer Res., 52, pp 6692-6695, 1992; Phang et al., Cancer Res., 53, pp 5977-5981, 1993; and Critchfield et al., Biochem. Pharmacol., 48, pp 1437-1445, 1994). There has also been reported that organic isothiocyanates found in a variety of edible plants suppress the formation of chemical carcinogens in animal models to thereby prevent carcinogenesis (Talalay et al., Biochem. Soc. Trans., 24, pp 806-810, 1996; and Zhang et al., Cancer Res. (suppl), 54, pp 1976-1981, 1994).
Compounds of the present invention are a xanthone compound having structural connection with anthraquinone and may be obtained in a relatively abundant amount from the fruit skin, tree bark or dried latex of guttiferaeous plants such as mangosteen (Garcinia mangostana L.). It is known that xanthone compounds have an anticancer action (G. W. Rewcastle et al., J. Med. Chem. 32, pp 793-799. 1989), an anti-inflammatory action (C. N. Lin et al., J. Pharm. Pharmacol. 48 pp 532-538, 1996), an antibacterial action (H. Hambloch et al., Eur. J. Med. Chem. 20, pp 71-77. 1985) and other pharmacological actions (H. Marona et al., Pharmazie, 53, pp 219-223, 1998; I. J. Chen et al., Gen. Pharmacol, 24, pp 1425-1433, 1993; and L. W. Wang et al., Bioorg. Med. Chem., 10, pp 567-572, 2002), depending on the position of a xanthone ring.
However, despite continued research on substances isolated from mangosteen, there has been no teaching or suggestion regarding uses of xanthone structural derivatives as a chemosensitizer which specifically acts on cancer cells having resistance to conventional anticancer drugs by exhibiting an inhibitory action against the P-gp activity.